Abiological Self-Assembly

非生物自组装

• 批准号: 8180793
• 负责人: Peter J Stang
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8180793
• 关键词: Affinity; Antifreeze Proteins; Antineoplastic Agents; Binding; Biochemical; Biological; Biological Process; Cell surface; Chemical Agents; Chemistry; Cilengitide; Complement; Complex; Cyclophosphamide; Disease; Doxorubicin; Drug Delivery Systems; Endothelium; Enzymes; Fluorouracil; Future; Gene Expression Regulation; Goals; Grant; Heart; Human; In Vitro; Integrins; Investigation; Kinetics; Life; Ligands; Literature; Medical; Membrane; Metals; Methodology; Methods; Microtubules; Modeling; Nucleic Acids; Organism; Pharmaceutical Preparations; Phospholipids; Preparation; Prevention; Process; Production; Progress Reports; Property; Proteins; Publishing; Research; Research Personnel; Ribosomes; Shapes; Specificity; Structure; System; Thermodynamics; Transfection; antitumor agent; base; chemotherapy; chymotrypsin; design; improved; innovation; insight; molecular recognition; nanoscale; novel; novel strategies; protein folding; repaired; self assembly; small molecule; tool; tumor

DESCRIPTION (provided by applicant): The broad long term objectives of this research are: (1) to develop efficient, new methods for the preparation of complex nanoscale molecules with well-defined shapes and sizes, by rational design, using abiological self- assembly; (2) to provide insights and gain a better understanding of molecular recognition phenomena and self-assembly processes; (3) to develop abiological self-assembly as a platform for novel biomedical applications. [Our specific goals are to: (a) examine encapsulation and host-guest interactions of small drug- like organic molecules, as well as the encapsulation of three diverse, widely-used commercially-available cancer drugs (fluorouracil, cyclophosphamide, doxorubicin); (b) study protein and enzyme encapsulation by pre-designed self-assembled metallacages; (c) develop targeted drug delivery methodologies via self- assembled metallacages and the multivalent display of peptidic (and other) integrin antagonists.] We will use abiological, coordination-driven and our "directional bonding" approach to achieve these aims. This methodology allows for the rapid, pre-designed, (rational) self-assembly of nanoscale systems with well- defined shapes and sizes, due to metal d-orbital involvement that allows dative, metal-ligand bonds to be highly directional. Moreover, coordination kinetics can be modulated to engage in self-repair to achieve thermodynamic control of the desired, pre-designed super structures. Self-assembly is at the heart of countless biological processes that all living organisms, from the simplest to humans, depend upon. Protein folding, nucleic acid assembly and tertiary structures, ribosomes, phospholipid membranes and microtubules are but representative examples of self-assembly. Insights gained from the proposed abiological self-assembly studies will be applicable to a better and more complete understanding of the complex, not well-understood biological self-assembly processes. If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders. PUBLIC HEALTH RELEVANCE: If the aims of this application are achieved, biomedical researchers will have new tools and entirely new approaches for the formation of large, nanoscale, complex molecules with unique properties that will complement and enhance classical covalent synthetic methods. As a consequence, in the long term, these approaches will facilitate the discovery and production of improved chemical agents and chemotherapy for the treatment and possible prevention of medical disorders and in particular. Additionally, in the future, innovative transfection systems and possible gene-regulation may evolve from these discoveries.

描述（由申请人提供）：本研究的广泛长期目标是：（1）开发高效的新方法，通过合理设计，使用非生物自组装来制备具有明确形状和尺寸的复杂纳米级分子。 ; （2）提供见解并更好地理解分子识别现象和自组装过程； (3)开发非生物自组装作为新型生物医学应用的平台。 [我们的具体目标是：(a) 检查类药物有机小分子的封装和主客体相互作用，以及三种不同的、广泛使用的市售抗癌药物（氟尿嘧啶、环磷酰胺、阿霉素）的封装； (b) 通过预先设计的自组装金属笼研究蛋白质和酶的封装； （c）通过自组装金属基和肽（和其他）整联蛋白拮抗剂的多价展示来开发靶向药物递送方法。]我们将使用非生物的、协调驱动的和我们的“定向结合”方法来实现这些目标。该方法允许快速、预先设计、（合理）自组装具有明确形状和尺寸的纳米级系统，因为金属 d 轨道的参与使得配位的金属-配体键具有高度的方向性。此外，可以调节配位动力学以进行自我修复，从而实现对所需的预先设计的超级结构的热力学控制。自组装是所有生物体（从最简单的生物体到人类）所依赖的无数生物过程的核心。蛋白质折叠、核酸组装和三级结构、核糖体、磷脂膜和微管只是自组装的代表性例子。从拟议的生物自组装研究中获得的见解将适用于更好、更全面地理解复杂的、尚未充分理解的生物自组装过程。如果这一应用的目标得以实现，生物医学研究人员将拥有新的工具和全新的方法来形成具有独特性质的大型纳米级复杂分子，这将补充和增强经典的共价合成方法。因此，从长远来看，这些方法将有助于发现和生产改进的化学制剂和化疗，以治疗和可能预防医学疾病。 公共健康相关性：如果该应用的目标得以实现，生物医学研究人员将拥有新的工具和全新的方法来形成具有独特性质的大型纳米级复杂分子，这些分子将补充和增强经典的共价合成方法。因此，从长远来看，这些方法将有助于发现和生产改进的化学制剂和化疗，用于治疗和可能预防医学疾病，特别是。此外，在未来，创新的转染系统和可能的基因调控可能会从这些发现中发展出来。